Browsing by Author "Kraft, Peter"
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Item Explicit Modeling of Ancestry Improves Polygenic Risk Scores and BLUP Prediction(Wiley, 2015-09) Chen, Chia-Yen; Han, Jiali; Hunter, David J.; Kraft, Peter; Price, Alkes L.; Department of Epidemiology, Richard M. Fairbanks School of Public HealthPolygenic prediction using genome-wide SNPs can provide high prediction accuracy for complex traits. Here, we investigate the question of how to account for genetic ancestry when conducting polygenic prediction. We show that the accuracy of polygenic prediction in structured populations may be partly due to genetic ancestry. However, we hypothesized that explicitly modeling ancestry could improve polygenic prediction accuracy. We analyzed three GWAS of hair color (HC), tanning ability (TA), and basal cell carcinoma (BCC) in European Americans (sample size from 7,440 to 9,822) and considered two widely used polygenic prediction approaches: polygenic risk scores (PRSs) and best linear unbiased prediction (BLUP). We compared polygenic prediction without correction for ancestry to polygenic prediction with ancestry as a separate component in the model. In 10-fold cross-validation using the PRS approach, the R(2) for HC increased by 66% (0.0456-0.0755; P < 10(-16)), the R(2) for TA increased by 123% (0.0154 to 0.0344; P < 10(-16)), and the liability-scale R(2) for BCC increased by 68% (0.0138-0.0232; P < 10(-16)) when explicitly modeling ancestry, which prevents ancestry effects from entering into each SNP effect and being overweighted. Surprisingly, explicitly modeling ancestry produces a similar improvement when using the BLUP approach, which fits all SNPs simultaneously in a single variance component and causes ancestry to be underweighted. We validate our findings via simulations, which show that the differences in prediction accuracy will increase in magnitude as sample sizes increase. In summary, our results show that explicitly modeling ancestry can be important in both PRS and BLUP prediction.Item Genome-wide analysis identifies 12 loci influencing human reproductive behavior(Nature, 2016-10) Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J.; Tropf, Felix C.; Shen, Xia; Wilson, James F.; Chasman, Daniel I.; Nolte, Ilja M.; Tragante, Vinicius; van der Laan, Sander W.; Perry, John R. B.; Kong, Augustine; Ahluwalia, Tarunveer; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F.; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J.; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F.; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J.; Gieger, Christian; Gunderson, Erica P.; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K.; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A.; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F.; McMahon, George; Meddens, S. Fleur W.; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A.; Monnereau, Claire; van der Most, Peter J.; Myhre, Ronny; Nalls, Mike A.; Nutile, Teresa; Panagiota, Kalafati Ioanna; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B.; Rich-Edwards, Janet; Rietveld, Cornelius A.; Robino, Antonietta; Rose, Lynda M.; Rueedi, Rico; Ryan, Kathy; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A.; Stolk, Lisette; Streeten, Elizabeth; Tonjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellman, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V.; Amin, Najaf; Andrews, Howard; Balkau, Beverly; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I.; Buring, Julie E.; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R.; Cucca, Francesco; Daniela, Toniolo; Davey-Smith, George; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M.; de Geus, Eco J. C.; Eriksson, Johan G.; Evans, Denis A.; Faul, Jessica D.; Felicita, Sala Cinzia; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J. F.; de Haan, Hugoline G.; Haerting, Johannes; Harris, Tamara B.; Heath, Andrew C.; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G.; Hopper, John; Hypponen, Elina; Jacobsson, Bo; Jaddoe, Vincent W.; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L. R.; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William; Lai, Sandra; Lehtimäki, Terho; Liewald, David C.; Lindgren, Cecilia; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K. E.; Martin, Nicholas G.; McGue, Matt; McQuillan, Ruth; Medland, Sarah E.; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Michela, Traglia; Milani, Lili; Mitchell, Paul; Montgomery, Grant W.; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A.; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K.; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda W. J. H.; Perola, Markus; Peyser, Patricia A.; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J.; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M.; Ring, Susan M.; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D.; Starr, John M.; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A.; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tönjes, Anke; Tung, Joyce Y.; Uitterlinden, André G.; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G.; Wang, Jie Jin; Wareham, Nicholas J.; Weir, David R.; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F.; Zondervan, Krina T.; Stefannson, Kari; Krueger, Robert F.; Lee, James J.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C.; Department of Epidemiology, Richard M. Fairbanks School of Public HealthThe genetic architecture of human reproductive behavior—age at first birth (AFB) and number of children ever born (NEB)—has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.Item Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma(SpringerNature, 2016-08-19) Chahal, Harvind S.; Wu, Wenting; Ransohoff, Katherine J.; Yang, Lingyao; Hedlin, Haley; Desai, Manisha; Lin, Yuan; Dai, Hong-Ji; Qureshi, Abrar A.; Li, Wen-Qing; Kraft, Peter; Hinds, David A.; Tang, Jean Y.; Han, Jiali; Sarin, Kavita Y.; Department of Epidemiology, Richard M. Fairbanks School of Public HealthBasal cell carcinoma (BCC) is the most common cancer worldwide with an annual incidence of 2.8 million cases in the United States alone. Previous studies have demonstrated an association between 21 distinct genetic loci and BCC risk. Here, we report the results of a two-stage genome-wide association study of BCC, totalling 17,187 cases and 287,054 controls. We confirm 17 previously reported loci and identify 14 new susceptibility loci reaching genome-wide significance (P<5 × 10(-8), logistic regression). These newly associated SNPs lie within predicted keratinocyte regulatory elements and in expression quantitative trait loci; furthermore, we identify candidate genes and non-coding RNAs involved in telomere maintenance, immune regulation and tumour progression, providing deeper insight into the pathogenesis of BCC.Item Genome-wide association study identifies 48 common genetic variants associated with handedness(Springer Nature, 2021) Cuellar-Partida, Gabriel; Tung, Joyce Y.; Eriksson, Nicholas; Albrecht, Eva; Aliev, Fazil; Andreassen, Ole A.; Barroso, Inês; Beckmann, Jacques S.; Boks, Marco P.; Boomsma, Dorret I.; Boyd, Heather A.; Breteler, Monique M. B.; Campbell, Harry; Chasman, Daniel I.; Cherkas, Lynn F.; Davies, Gail; de Geus, Eco J. C.; Deary, Ian J.; Deloukas, Panos; Dick, Danielle M.; Duffy, David L.; Eriksson, Johan G.; Esko, Tõnu; Feenstra, Bjarke; Geller, Frank; Gieger, Christian; Giegling, Ina; Gordon, Scott D.; Han, Jiali; Hansen, Thomas F.; Hartmann, Annette M.; Hayward, Caroline; Heikkilä, Kauko; Hicks, Andrew A.; Hirschhorn, Joel N.; Hottenga, Jouke-Jan; Huffman, Jennifer E.; Hwang, Liang-Dar; Ikram, M. Arfan; Kaprio, Jaakko; Kemp, John P.; Khaw, Kay-Tee; Klopp, Norman; Konte, Bettina; Kutalik, Zoltan; Lahti, Jari; Li, Xin; Loos, Ruth J. F.; Luciano, Michelle; Magnusson, Sigurdur H.; Mangino, Massimo; Marques-Vidal, Pedro; Martin, Nicholas G.; McArdle, Wendy L.; McCarthy, Mark I.; Medina-Gomez, Carolina; Melbye, Mads; Melville, Scott A.; Metspalu, Andres; Milani, Lili; Mooser, Vincent; Nelis, Mari; Nyholt, Dale R.; O'Connell, Kevin S.; Ophoff, Roel A.; Palmer, Cameron; Palotie, Aarno; Palviainen, Teemu; Pare, Guillaume; Paternoster, Lavinia; Peltonen, Leena; Penninx, Brenda W. J. H.; Polasek, Ozren; Pramstaller, Peter P.; Prokopenko, Inga; Raikkonen, Katri; Ripatti, Samuli; Rivadeneira, Fernando; Rudan, Igor; Rujescu, Dan; Smit, Johannes H.; Smith, George Davey; Smoller, Jordan W.; Soranzo, Nicole; Spector, Tim D.; St. Pourcain, Beate; Starr, John M.; Stefánsson, Hreinn; Steinberg, Stacy; Teder-Laving, Maris; Thorleifsson, Gudmar; Stefánsson, Kári; Timpson, Nicholas J.; Uitterlinden, André G.; van Duijn, Cornelia M.; van Rooij, Frank J. A.; Vink, Jaqueline M.; Vollenweider, Peter; Vuoksimaa, Eero; Waeber, Gérard; Wareham, Nicholas J.; Warrington, Nicole; Waterworth, Dawn; Werge, Thomas; Wichmann, H-Erich; Widen, Elisabeth; Willemsen, Gonneke; Wright, Alan F.; Wright, Margaret J.; Xu, Mousheng; Zhao, Jing Hua; Kraft, Peter; Hinds, David A.; Lindgren, Cecilia M.; Mägi, Reedik; Neale, Benjamin M.; Evans, David M.; Medland, Sarah E.; Epidemiology, School of Public HealthHandedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P < 5 × 10-8) with left-handedness and 7 associated with ambidexterity. Tissue-enrichment analysis implicated the CNS in the aetiology of handedness. Pathways including regulation of microtubules and brain morphology were also highlighted. We found suggestive positive genetic correlations between left-handedness and neuropsychiatric traits, including schizophrenia and bipolar disorder. Furthermore, the genetic correlation between left-handedness and ambidexterity is low (rG = 0.26), which implies that these traits are largely influenced by different genetic mechanisms. Our findings suggest that handedness is highly polygenic and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders.Item Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma(SpringerNature, 2016-07-18) Chahal, Harvind S.; Lin, Yuan; Ransohoff, Katherine J.; Hinds, David A.; Wu, Wenting; Dai, Hong-Ji; Qureshi, Abrar A.; Li, Wen-Qing; Kraft, Peter; Tang, Jean Y.; Han, Jiali; Sarin, Kavita Y.; Department of Epidemiology, Richard M. Fairbanks School of Public HealthCutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7-11% of Caucasians in the United States. The genetic determinants of susceptibility to cutaneous squamous cell carcinoma remain largely unknown. Here we report the results of a two-stage genome-wide association study of cutaneous squamous cell carcinoma, totalling 7,404 cases and 292,076 controls. Eleven loci reached genome-wide significance (P<5 × 10(-8)) including seven previously confirmed pigmentation-related loci: MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and BNC2. We identify an additional four susceptibility loci: 11q23.3 CADM1, a metastasis suppressor gene involved in modifying tumour interaction with cell-mediated immunity; 2p22.3; 7p21.1 AHR, the dioxin receptor involved in anti-apoptotic pathways and melanoma progression; and 9q34.3 SEC16A, a putative oncogene with roles in secretion and cellular proliferation. These susceptibility loci provide deeper insight into the pathogenesis of squamous cell carcinoma.Item Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels(Nature Publishing Group, 2018-01-17) Jiang, Xia; O’Reilly, Paul F.; Aschard, Hugues; Hsu, Yi-Hsiang; Richards, J. Brent; Dupuis, Josée; Ingelsson, Erik; Karasik, David; Pilz, Stefan; Berry, Diane; Kestenbaum, Bryan; Zheng, Jusheng; Luan, Jianan; Sofianopoulou, Eleni; Streeten, Elizabeth A.; Albanes, Demetrius; Lutsey, Pamela L.; Yao, Lu; Tang, Weihong; Econs, Michael J.; Wallaschofski, Henri; Völzke, Henry; Zhou, Ang; Power, Chris; McCarthy, Mark I.; Michos, Erin D.; Boerwinkle, Eric; Weinstein, Stephanie J.; Freedman, Neal D.; Huang, Wen-Yi; Van Schoor, Natasja M.; Velde, Nathalie van der; de Groot, Lisette C. P. G. M.; Enneman, Anke; Cupples, L. Adrienne; Booth, Sarah L.; Vasan, Ramachandran S.; Liu, Ching-Ti; Zhou, Yanhua; Ripatti, Samuli; Ohlsson, Claes; Vandenput, Liesbeth; Lorentzon, Mattias; Eriksson, Johan G.; Shea, M. Kyla; Houston, Denise K.; Kritchevsky, Stephen B.; Liu, Yongmei; Lohman, Kurt K.; Ferrucci, Luigi; Peacock, Munro; Gieger, Christian; Beekman, Marian; Slagboom, Eline; Deelen, Joris; Heemst, Diana van; Kleber, Marcus E.; März, Winfried; de Boer, Ian H.; Wood, Alexis C.; Rotter, Jerome I.; Rich, Stephen S.; Robinson-Cohen, Cassianne; Heijer, Martin den; Jarvelin, Marjo-Riitta; Cavadino, Alana; Joshi, Peter K.; Wilson, James F.; Hayward, Caroline; Lind, Lars; Michaëlsson, Karl; Trompet, Stella; Zillikens, M. Carola; Uitterlinden, Andre G.; Rivadeneira, Fernando; Broer, Linda; Zgaga, Lina; Campbell, Harry; Theodoratou, Evropi; Farrington, Susan M.; Timofeeva, Maria; Dunlop, Malcolm G.; Valdes, Ana M.; Tikkanen, Emmi; Lehtimäki, Terho; Lyytikäinen, Leo-Pekka; Kähönen, Mika; Raitakari, Olli T.; Mikkilä, Vera; Ikram, M. Arfan; Sattar, Naveed; Jukema, J. Wouter; Wareham, Nicholas J.; Langenberg, Claudia; Forouhi, Nita G.; Gundersen, Thomas E.; Khaw, Kay-Tee; Butterworth, Adam S.; Danesh, John; Spector, Timothy; Wang, Thomas J.; Hyppönen, Elina; Kraft, Peter; Kiel, Douglas P.; Medicine, School of MedicineVitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levelsItem Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color(American Association for the Advancement of Science, 2021-03-10) Simcoe, Mark; Valdes, Ana; Liu, Fan; Furlotte, Nicholas A.; Evans, David M.; Hemani, Gibran; Ring, Susan M.; Smith, George Davey; Duffy, David L.; Zhu, Gu; Gordon, Scott D.; Medland, Sarah E.; Vuckovic, Dragana; Girotto, Giorgia; Sala, Cinzia; Catamo, Eulalia; Concas, Maria Pina; Brumat, Marco; Gasparini, Paolo; Toniolo, Daniela; Cocca, Massimiliano; Robino, Antonietta; Yazar, Seyhan; Hewitt, Alex; Wu, Wenting; Kraft, Peter; Hammond, Christopher J.; Shi, Yuan; Chen, Yan; Zeng, Changqing; Klaver, Caroline C. W.; Uitterlinden, Andre G.; Ikram, M. Arfan; Hamer, Merel A.; van Duijn, Cornelia M.; Nijsten, Tamar; Han, Jiali; Mackey, David A.; Martin, Nicholas G.; Cheng, Ching-Yu; 23andMe Research Team; International Visible Trait Genetics Consortium; Hinds, David A.; Spector, Timothy D.; Kayser, Manfred; Hysi, Pirro G.; Epidemiology, School of Public HealthHuman eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.Item Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma(Nature Research, 2020-02-10) Sarin, Kavita Y.; Lin, Yuan; Daneshjou, Roxana; Ziyatdinov, Andrey; Thorleifsson, Gudmar; Rubin, Adam; Pardo, Luba M.; Wu, Wenting; Khavari, Paul A.; Uitterlinden, Andre; Nijsten, Tamar; Toland, Amanda E.; Olafsson, Jon H.; Sigurgeirsson, Bardur; Thorisdottir, Kristin; Jorgensen, Eric; Whittemore, Alice S.; Kraft, Peter; Stacey, Simon N.; Stefansson, Kari; Asgari, Maryam M.; Han, Jiali; Epidemiology, School of Public HealthCutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.Item Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk(Nature, 2017) Day, Felix R.; Thompson, Deborah J.; Helgason, Hannes; Chasman, Daniel I.; Finucane, Hilary; Sulem, Patrick; Ruth, Katherine S.; Whalen, Sean; Sarkar, Abhishek K.; Albrecht, Eva; Altmaier, Elisabeth; Amini, Marzyeh; Barbieri, Caterina M.; Boutin, Thibaud; Campbell, Archie; Demerath, Ellen; Giri, Ayush; He, Chunyan; Hottenga, Jouke J.; Karlsson, Robert; Kolchic, Ivana; Loh, Po-Ru; Lunetta, Kathryn L.; Mangino, Massimo; Marco, Brumat; McMahon, George; Medland, Sarah E.; Nolte, Ilja M.; Noordam, Raymond; Nutile, Teresa; Paternoster, Lavinia; Perjakova, Natalia; Porcu, Eleonora; Rose, Lynda M.; Schraut, Katharina E.; Segrè, Ayellet V.; Smith, Albert V.; Stolk, Lisette; Teumer, Alexander; Andrulis, Irene L.; Bandinelli, Stefania; Beckmann, Matthias W.; Benitez, Javier; Bergmann, Sven; Bochud, Murielle; Boerwinkle, Eric; Bojesen, Stig E.; Bolla, Manjeet K.; Brand, Judith S.; Brauch, Hiltrud; Brenner, Hermann; Broer, Linda; Brüning, Thomas; Buring, Julie E.; Campbell, Harry; Catamo, Eulalia; Chanock, Stephen; Chenevix-Trench, Georgia; Corre, Tanguy; Couch, Fergus J.; Cousminer, Diana L.; Cox, Angela; Crisponi, Laura; Czene, Kamila; Davey-Smith, George; de Geus, Eco J. C. N.; de Mutsert, Renée; De Vivo, Immaculata; Dennis, Joe; Devilee, Peter; dos-Santos-Silva, Isabel; Dunning, Alison M.; Eriksson, Johan G.; Fasching, Peter A.; Fernández-Rhodes, Lindsay; Ferrucci, Luigi; Flesch-Janys, Dieter; Franke, Lude; Gabrielson, Marike; Gandin, Ilaria; Giles, Graham G.; Grallert, Harald; Gudbjartsson, Daniel F.; Guéne, Pascal; Hall, Perr; Hallberg, Emily; Hamann, Ute; Harris, Tamara B.; Hartman, Catharina A.; Heiss, Gerardo; Hooning, Maartje J.; Hopper, John L.; Hu, Frank; Hunter, David; Ikram, M. Arfan; Im, Hae Kyung; Järvelin, Marjo-Riitta; Joshi, Peter K.; Karasik, David; Kutalik, Zoltan; LaChance, Genevieve; Lambrechts, Diether; Langenberg, Claudia; Launer, Lenore J.; Laven, Joop S. E.; Lenarduzzi, Stefania; Li, Jingmei; Lind, Penelope A.; Lindstrom, Sara; Liu, YongMei; Luan, Jian'an; Mannermaa, Arto; Mbarek, Hamdi; McCarthy, Mark I.; Meisinger, Christa; Meitinger, Thomas; Menni, Cristina; Metspalu, Andres; Michailidou, Kyriaki; Milani, Lili; Milne, Roger L.; Montgomery, Grant W.; Mulligan, Anna M.; Nalls, Mike A.; Navarro, Pau; Nevanlinna, Heli; Nyholt, Dale R.; Oldehinkel, Albertine J.; O'Mara, Tracy A.; Padmanabhan, Sandosh; Palotie, Aarno; Pedersen, Nancy; Peters, Annette; Peto, Julian; Pharoah, Paul D. P.; Pouta, Anneli; Radice, Paolo; Rahman, Iffat; Ring, Susan M.; Robino, Antonietta; Rosendaal, Frits R.; Rudan, Igor; Rueedi, Rico; Ruggiero, Daniela; Sala, Cinzia F.; Schmidt, Marjanka K.; Scott, Robert A.; Shah, Mitul; Sorice, Rossella; Southey, Melissa C.; Sovio, Ulla; Stampfer, Meir; Steri, Maristella; Strauch, Konstantin; Tanaka, Toshiko; Tikkanen, Emmi; Timpson, Nicholas J.; Traglia, Michela; Truong, Thérèse; Tyrer, Jonathan P.; Uitterlinden, André G.; Edwards, Digna R. Velez; Vitart, Veronique; Völker, Uwe; Vollenweider, Peter; Wang, Qin; Widen, Elisabeth; van Dijk, Ko Willems; Willemsen, Gonneke; Winqvist, Robert; Wolffenbuttel, Bruce H. R.; Zhao, Jing Hua; Zoledziewska, Magdalena; Zygmunt, Marek; Alizadeh, Behrooz Z.; Boomsma, Dorret I.; Ciullo, Marina; Cucca, Francesco; Esko, Tõnu; Franceschini, Nora; Gieger, Christian; Gudnason, Vilmundur; Hayward, Caroline; Kraft, Peter; Lawlor, Debbie A.; Magnusson, Patrik K. E.; Martin, Nicholas G.; Mook-Kanamori, Dennis O.; Nohr, Ellen A.; Polasek, Ozren; Porteous, David; Price, Alkes L.; Ridker, Paul M.; Snieder, Harold; Spector, Tim D.; Stöckl, Doris; Toniolo, Daniela; Ulivi, Sheila; Visser, Jenny A.; Völzke, Henry; Wareham, Nicholas J.; Wilson, James F.; Spurdle, Amanda B.; Thorsteindottir, Unnur; Pollard, Katherine S.; Easton, Douglas F.; Tung, Joyce Y.; Chang-Claude, Jenny; Hinds, David; Murray, Anna; Murabito, Joanne M.; Stefansson, Kari; Ong, Ken K.; Perry, John R. B.; The Lifelines Cohort Study; The InterAct Consortium; kConFab/AOCS Investigators; Endometrial Cancer Association Consortium; Ovarian Cancer Association Consortium; PRACTICAL consortium; Epidemiology, School of Public HealthThe timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10−8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.Item Height, nevus count, and risk of cutaneous malignant melanoma: Results from 2 large cohorts of US women(Elsevier, 2020) Li, Xin; Kraft, Peter; De Vivo, Immaculata; Giovannucci, Edward; Liang, Liming; Nan, Hongmei; Epidemiology, School of Public HealthBackground: Taller individuals are at higher risk of melanoma. Objective: To prospectively investigate the association of height with nevus count and melanoma and estimate the proportion of height-melanoma association explained by nevus count among white participants from the Nurses' Health Study (NHS) and Nurses' Health Study 2 (NHS2). Methods: We used Cox proportional hazards regression and multinomial logistic regression for data analyses, with adjustment of potential confounders in the multivariate model. Results: We included 82,468 and 106,069 women from NHS and NHS2, respectively. The hazard ratio was 1.21 (95% confidence interval [CI] 1.12-1.31) for the association between every 10-cm increase in height and melanoma. Compared with women with no nevi, the odds ratios (95% CIs) associated with a 10-cm increase in height were 1.35 (95% CI 1.23-1.48) in the NHS and 1.12 (95% CI 1.09-1.15) in the NHS2 for women with greater than or equal to 10 moles. The proportion of excess melanoma risk associated with each 10-cm increase in height explained by nevus count was 8.03% in the NHS and 10.22% in the NHS2. Limitation: Self-reported height and nevus count. Mole counts were limited to 1 arm or both legs. Conclusion: Nevus count is an important explanatory factor for the excess risk of melanoma among taller white women.